Li, J.-Y. | Search bioRxiv

bioRxiv2020

Low-protein/high-carbohydrate diet induces AMPK-dependent canonical and non-canonical thermogenic response in subcutaneous adipose tissue

Low-protein/high-carbohydrate (LPHC) diet promotes metabolic health and longevity in adult humans and animal models. However, the complex molecular underpinnings of how LPHC diet leads to metabolic benefits remain elusive. Through a multi-layered approach, here we observed that LPHC diet promotes an energy-dissipating response consisting in the parallel recruitment of canonical and non-canonical (muscular) thermogenic systems in subcutaneous white adipose tissue (sWAT). In particular, we measured Ucp1 induction in association with up-regulation of actomyosin components and several Serca (Serca1, Serca2a, Serca2b) ATPases. In beige adipocytes, we observed that AMPK activation is responsible for transducing the amino acid lowering in an enhanced fat catabolism, which sustains both Ucp1- and Serca-dependent energy dissipation. Limiting AMPK activation counteracts the expression of brown fat and muscular genes, including Ucp1 and Serca, as well as mitochondrial oxidative genes. We observed that mitochondrial reactive oxygen species are the upstream molecules controlling AMPK-mediated metabolic rewiring in amino acid-restricted beige adipocytes. Our findings delineate a novel metabolic phenotype of responses to amino acid shortage, which recapitulates some of the benefits of cool temperature in sWAT. In conclusion, this highlights LPHC diet as a valuable and practicable strategy to prevent metabolic diseases through the enhancement of mitochondrial oxidative metabolism and the recruitment of different energy dissipating routes in beige adipocytes.

physiology↗

bioRxiv2019

Integrative model to coordinate the oligomerization and aggregation mechanisms of CCL5

The CC-type chemokine ligand 5 (CCL5) is involved in the pathogenesis of many inflammatory conditions. The oligomerization and aggregation of CCL5 are considered to be responsible for its inflammatory properties. The CC-type dimer acts as the basic unit to constitute the oligomer. However, the structural basis of CCL5 oligomerization remains controversial. In this study, NMR and biophysical analyses proposed evidence that no single dimer-dimer interaction dominates in the oligomerization process of CCL5. CCL5 could oligomerize alternatively through two different interactions, E66-K25 and E66-R44/K45. In addition, a newly determined trimer structure reported an interfacial interaction through the N-terminal 12FAY14 sequence. The interaction contributes to aggregation and precipitation. In accordance with the observations, an integrative model explains the CCL5 oligomerization and aggregation process. CCL5 assembly consists of two types of dimer-dimer interactions and one aggregation mechanism. For full-length CCL5, the molecular accumulation triggers oligomerization through the E66-K25 interaction, and the 12FAY14 interaction acts as a secondary effect to derive aggregation. The E66-R44/K45 interaction dominates in CCL5 N-terminal truncations. The interaction would lead to filament-like formation in solution.

biochemistry↗